PACES trial: Evaluating the effectiveness of eflornithine and sulindac in preventing colon adenomas

There are more than 1 million survivors of colorectal cancer in the U.S. today, and the number continues to grow. After completing treatment for colorectal cancer and being deemed cancer-free, these patients remain at higher risk of developing precancerous polyps or a second colorectal cancer than the general population.

Prevention is preferable to treatment, but it relies on identification of an appropriate patient population. For colorectal cancer, patients who have survived their index tumor are easily identified and are motivated to participate in studies aimed at the prevention of further disease.

Polyamines are naturally occurring substances that, in excess, promote carcinogenesis within colorectal tissues. When used together, eflornithine and sulindac lower colorectal tissue polyamine levels and have shown early promise in preventing carcinogenesis in mouse models and in humans. Importantly, these oral agents effectively prevent colorectal carcinogenesis when given at very low dosages, resulting in minimal toxicity.

Putting drugs through the paces

The S0820 Preventing Adenomas of the Colon with Eflornithine and Sulindac (PACES) study seeks to determine whether two drugs that have shown early promise can significantly lower the risk of secondary colorectal polyp or cancer for these survivors.

PACES study researchers are enrolling approximately 1,500 patients who have recently completed surgery (with or without radiation, chemotherapy) for Stage 0—III colorectal cancer. Approximately one year after resection (six–15 months), patients will be randomized to either eflornithine 500mg/day alone, sulindac 150mg/day alone, eflornithine 500mg/day of eflornithine with 150mg/day of sulindac, or two placebos daily for three years. They will then have a colonoscopy (for example, at study-year three, which corresponds to postoperative year four). Audiograms are done pre- and post-intervention, and the audiology eligibility criteria used in S0820/PACES are more stringent than those used in the previous phase III trial of adenoma patients. Investigators are looking to learn whether either drug or the combination reduces the rate of high-risk adenomas or second primary colorectal cancers in these cancer survivors. Patients will then have annual check-ups for five years off drug intervention and undergo follow-up colonoscopy eight years after enrolling.

A previous phase III clinical trial in 2008 showed that 267 patients who had had adenomas removed from their colon and then took daily eflornithine and sulindac at these dosages for three years lowered their risk of developing another adenoma by 70 percent compared with those who did not take the drugs.* More importantly, the adenomas that were most likely to be prevented were the ones that are most likely to become colon cancer—that is, high-risk adenomas. Patients in this trial showed a 90 percent decreased chance of developing a high-risk adenoma. In that study, no significant differences were detected in gastrointestinal, cardiovascular, or other toxicity, including hearing loss, which has been associated with high doses of eflornithine. Subsequent longitudinal analyses, however, did reveal an 8 percent audiometric threshold deficit attributed to eflornithine after three years on-study (sub-clinical hearing loss). Otherwise, the agents were extremely well-tolerated.

Whereas this combination had substantial preventive effects in patients who had been treated for colorectal adenomas, PACES will address whether those observed benefits also extend to colon cancer survivors.

Testing eflornithine and sulindac

The two drugs being tested are not new, but neither has been approved by the U.S. Food and Drug Administration specifically for colorectal cancer prevention. Eflornithine (also known as difluoromethylornithine, or DFMO) has been used intravenously to treat trypanosomiasis, sometimes called “sleeping sickness,” and in a skin cream to reduce unwanted hair growth. Sulindac is a non-steroidal anti-inflammatory drug used to treat arthritis pain. It has been shown to reduce the number of colon polyps in patients with familial adenomatous polyposis, an inherited condition that leads to the development of hundreds, or even thousands, of such polyps.

More than 500 U.S. health care institutions are participating in the study. Interested physicians can find the nearest participating institution online at SWOG.org, at CTSU.org, or by contacting SWOG (formerly the Southwest Oncology Group,) at 210-614-8808 or protocols@swog.org. The trial is funded by the National Cancer Institute, Division of Cancer Prevention.

We can do more to prevent cancers by targeting the groups at greater risk. Colorectal cancer survivors in particular stand to benefit from further risk reduction strategies.